| 16403852 |
Rosenfeld CA, Sultatos LG: Concentration-dependent kinetics of acetylcholinesterase inhibition by the organophosphate paraoxon. Toxicol Sci. 2006 Apr;90(2):460-9. Epub 2006 Jan 10.
For decades the interaction of the anticholinesterase organophosphorus compounds with acetylcholinesterase has been characterized as a straightforward phosphylation of the active site serine (Ser-203) which can be described kinetically by the inhibitory rate constant k (i). However, more recently certain kinetic complexities in the inhibition of acetylcholinesterase by organophosphates such as paraoxon (O,O-diethyl O-(p-nitrophenyl) phosphate) and chlorpyrifos oxon (O,O-diethyl O-(3,5,6-trichloro-2-pyridyl) phosphate) have raised questions regarding the adequacy of the kinetic scheme on which k (i) is based. The present article documents conditions in which the inhibitory capacity of paraoxon towards human recombinant acetylcholinesterase appears to change as a function of oxon concentration (as evidenced by a changing k (i)), with the inhibitory capacity of individual oxon molecules increasing at lower oxon concentrations. Optimization of a computer model based on an Ordered Uni Bi kinetic mechanism for phosphylation of acetylcholinesterse determined k (1) to be 0.5 nM (-1) h (-1), and k (-1) to be 169.5 h (-1). These values were used in a comparison of the Ordered Uni Bi model versus a k (i) model in order to assess the capacity of k (i) to describe accurately the inhibition of acetylcholinesterase by paraoxon. Interestingly, the k (i) model was accurate only at equilibrium (or near equilibrium), and when the inhibitor concentration was well below its K (d) (pseudo first order conditions). Comparisons of the Ordered Uni Bi and k (i) models demonstrate the changing k (i) as a function of inhibitor concentrations is not an artifact resulting from inappropriate inhibitor concentrations. |
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